Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type plasma protease inhibitor that inhibits factor Xa and the factor VIIa/tissue factor catalytic complex. It plays an important role in feedback inhibition of the coagulation cascade (Broze, Annu Rev Med 46:103, 1995). TFPI has also been used successfully to prevent lethality and attenuate coagulopathic responses in a baboon model of septic shock (Creasey et al, J Clin invest 91:2850, 1993; and Carr et al, Circ Shock 44:126, 1995). However, the mechanism of reduced mortality in these animals could not be explained merely by the anticoagulant effect of TFPI, because TFPI-treated animals also had a significantly depressed interleukin-6 response. Moreover, inhibition of coagulopathic responses by other anticoagulants has failed to block the organ damage or lethal effect of endotoxic shock (Coalson et al, Circ Shock 5:423, 1978; Warr et al, Blood 75:1481, 1990; and Taylor et al, Blood 78:364, 1991). We show here that recombinant TFPI can bind to endotoxin in vitro, This binding prevents interaction of endotoxin with both lipopolysaccharide binding protein and CD14, thereby blocking cellular responses. (C) 1997 by The American Society of Hematology.